WO2007055418A1 - Derive spiro aza-substitue - Google Patents

Derive spiro aza-substitue Download PDF

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Publication number
WO2007055418A1
WO2007055418A1 PCT/JP2006/322911 JP2006322911W WO2007055418A1 WO 2007055418 A1 WO2007055418 A1 WO 2007055418A1 JP 2006322911 W JP2006322911 W JP 2006322911W WO 2007055418 A1 WO2007055418 A1 WO 2007055418A1
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WIPO (PCT)
Prior art keywords
group
trans
spiro
methyl
oxo
Prior art date
Application number
PCT/JP2006/322911
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English (en)
Japanese (ja)
Inventor
Makoto Jitsuoka
Daisuke Tsukahara
Nagaaki Sato
Original Assignee
Banyu Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP06832790A priority Critical patent/EP1953165B1/fr
Application filed by Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Priority to CA2629018A priority patent/CA2629018C/fr
Priority to AU2006312557A priority patent/AU2006312557B2/en
Priority to ES06832790T priority patent/ES2381205T3/es
Priority to NZ568292A priority patent/NZ568292A/en
Priority to US12/084,817 priority patent/US8158791B2/en
Priority to JP2007544242A priority patent/JP4371164B2/ja
Priority to CN200680041873.0A priority patent/CN101305009B/zh
Priority to BRPI0618354A priority patent/BRPI0618354B8/pt
Priority to KR1020087011108A priority patent/KR101318127B1/ko
Publication of WO2007055418A1 publication Critical patent/WO2007055418A1/fr
Priority to NO20082579A priority patent/NO20082579L/no
Priority to US13/396,887 priority patent/US20120149703A1/en

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    • C07—ORGANIC CHEMISTRY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Definitions

  • the present invention relates to aza-substituted spiro derivatives.
  • histamine a physiologically active endogenous factor
  • histamine a physiologically active endogenous factor
  • histamine is known to function as a neurotransmitter and have a wide range of pharmacological activities (eg, Life 'Shen (L ife Science), 17, .5.0, p. 3 (1 97 5 years)).
  • histaminergic nerves in the posterior hypothalamic nodular papillary nucleus is due to the physiological functions of histamine related to the hypothalamic function (sleep, wakefulness rhythm, endocrine, feeding / feeding behavior, sexual behavior, etc.) It has been suggested that it plays an important role in the regulation of the brain (see, for example, Progress 'N' Neurobiology, 6 3 ⁇ , 6 3 7 (2000)).
  • projections in the brain areas associated with maintaining wakefulness suggests a role in coordinating the wakefulness or wakefulness-sleep cycle.
  • the presence of projections on many marginal structures such as the hippocampus or tonsils-like complex suggests a role in the regulation of autonomic nerves, emotional, motivated behavioral control, and learning / memory processes. .
  • histamine When released from producer cells, histamine exerts its pharmacological action by acting on specific macromolecules called receptors on the cell membrane surface or in target cells, and regulates various body functions. .
  • histamine receptors four types have been discovered.
  • histamine H3 receptor as a receptor involved in central and peripheral nerve functions of histamine is various pharmacological and physiological studies. (For example, Trendsin Pharma Science Science, 8 to 24, 1 (1 (987))).
  • human and rodent histamine H 3 receptor genes have been identified in recent years and their existence has been elucidated (for example, molecular pharmacology).
  • Histamine H 3 receptors are present in the presynaptic membrane of central or peripheral neurons and function as autoreceptors, controlling histamine release and also controlling the release of other neurotransmitters. Yes. That is, it has been reported that histamine H 3 receptor agonists or antagonists or inverse agonists regulate the release of histamine, noradrenaline, serotonin, acetylcholine or dopamine from nerve endings. Yes.
  • neurotransmitters are suppressed by agonists such as (R) — ( ⁇ ) monomethylhistamine and is also promoted by antagonists or inverse agonists such as thioperamide (for example, see Trendsin Pharmacologica 1 Science, 19 September, 1 77 Hessy (1 998).
  • Examples similar to the compound of the present invention are disclosed in, for example, International Publication No. WO 99/22735.
  • the compounds disclosed herein have a carbonyl group in the portion corresponding to the present invention, whereas in the present invention, there is no carbonyl group in R. Therefore, it is different from the present invention.
  • the present invention relates to somatostatic agonists, and uses are also different from those of the present invention. '
  • the present invention has a histamine H 3 receptor antagonistic action (an action that inhibits binding of histamine to the histamine H 3 receptor) or an inverse action action (an action that suppresses the constitutive activity of the histamine H 3 receptor). It is an object of the present invention to provide a novel substance having an action as a histamine H 3 receptor antagonist ⁇ or inverse vasonis ⁇ in vivo.
  • the present inventors provide the following compounds or salts.
  • X, Y, Z and W each independently represent a methine group or a nitrogen atom which may have a substituent selected from the group consisting of the substituent group ⁇ , provided that X, ⁇ , ⁇ And all of W are not simultaneously a methine group which may have a substituent selected from the group consisting of the substituent group,
  • ⁇ represents one (C (R 3 ) (R 4 )) ml —, one C (O) one, one hundred _ or one N (R 5 ) —
  • B represents _N (SO ⁇ 1 ) one, -N (COR 2 ) ⁇ , _N (R 50 ) one,-O— or — C ( ⁇ ) one,
  • D represents one (C (R 30 ) (R 40 )) m2 —, — O—, —N (R 51 ) — or one C (O) —
  • 1111 and 1112 each independently represent 0 or 1
  • R ⁇ 13 ⁇ 4 2 and 1 5 each independently represents a hydrogen atom, a lower alkyl group, ⁇ aralkyl group or Ariru group,
  • R 3 , R 4 , 1 30 and 1 ⁇ 4 each independently represents a hydrogen atom, a hydroxyl group, a lower alkyl group, an aralkyl group or an aryl group;
  • Measures 5 () and 151 each independently represent a hydrogen atom or a lower alkyl group
  • Q represents a methine group or a nitrogen atom
  • R is the formula (II)
  • R 6 represents a hydrogen atom or a lower alkyl group
  • scales 7 and 8 each independently represent a lower alkyl group, a cycloalkyl group, an aralkyl group, a heteroaryl alkyl group, or R 7 , R 8 and the nitrogen atom to which they are bonded to each other to form a 4- to 8-membered nitrogen-containing aliphatic heterocyclic group
  • R 7 is C a and the nitrogen atom to which they are bonded to each other.
  • any hydrogen atom in the formula (II) is a lower alkyl group (the lower alkyl group may be substituted with a halogen atom, an oxo group or an alkoxy group) May be substituted with a substituent selected from the group consisting of a cycloalkyl group, a hydroxy group, an alkoxy group (the alkoxy group may be substituted with a halogen atom), and a halogen atom. .
  • a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt thereof.
  • a halogen atom, a hydroxy group, a lower alkyl group (the group includes a halogen atom, a hydro May be substituted with a xy group or an alkoxy group), a cycloalkyl group (the group may be substituted with a halogen atom, a hydroxy group or an alkoxy group), an alkoxy group (the group is a cycloalkyl group) Group, optionally substituted with a halogen atom or a hydroxyl group), an amino group, a cyano group, a mono- or di-lower alkylamino group, a formyl group, an alkanoyl group, a mono- or di-lower alkyl group ruberyl group, an aryl Rubamoyl group, heteroaryl rubamoyl group, allylalkylcarbamoyl group, heteroarylalkyl rubamoyl group, lower alkylsulfonyl group, lower alky
  • D is one (C (R 30 ) (R 40 )) m2 —, and m2 is 0 or 1, or a compound or a pharmaceutically acceptable salt thereof according to (1),
  • A is-C ( ⁇ )
  • B is-O- or 1 N (R 50 )-
  • D is 1 (C (R 30 ) (R 40 )) m2-
  • M 2 is 0 or 1.
  • A is one (C (R 3 ) (R 4 )) ml —
  • B is one 0—
  • D is one (C (R 30 ) (R 40 )) m2 —
  • ml Is 0 and m2 is 1.
  • A is – (C (R 3 ) (R 4 )) ml —, B is — C (O) —, D is — O—, — N (R 51 ) — or one (C 2.
  • R is the formula (11-1), (II-1), (II-13) or (II— 4) The compound according to (1) or a pharmaceutically acceptable salt thereof.
  • R has the formula (1 1 1), a (II one 4) or (II- 5), the compound or a pharmaceutically acceptable according to R 6 is a lower alkyl group (1) Salt.
  • R 7 and R 8 are joined together to form a lower alkyl group (which may be substituted with a halogen atom, an oxo group or an alkoxy group), a cycloalkyl group, and a hydroxy group.
  • a 4- to 8-membered nitrogen-containing aliphatic heterocyclic ring which may have a substituent selected from the group consisting of an alkoxy group (which may be substituted with a halogen atom) and a halogen atom
  • the compound or salt of the present invention acts as a histamine H3 receptor antagonist or inverse agonist in vivo. That is, the present invention provides a histamine H 3 receptor antagonist or inverse agonist comprising the compound according to (1) or a pharmaceutically acceptable salt thereof.
  • Histamine H 3 receptor has been found in recent studies to have a very high constitutive activity in receptor-expressing cells, tissues or expression, cells, tissue-derived membrane fractions, and even in vivo (endogenous agonists ( (Eg activity observed in the absence of histamine) (see, for example, Nature, 408, 860), and this constant activity is Has been reported to be suppressed.
  • endogenous agonists (Eg activity observed in the absence of histamine) (see, for example, Nature, 408, 860)
  • Eg activity observed in the absence of histamine see, for example, Nature, 408, 860
  • this constant activity is Has been reported to be suppressed.
  • thioperamide or siproxyphan suppresses the constitutive autoreceptor activity of the histamine H3 receptor, and consequently promotes the release and release of neurotransmitters (eg histamine) from nerve endings. .
  • thioperamide increases wakefulness in a dose-dependent manner and further reduces slow waves and REM sleep (eg, Life Science, 48, 2397 (1 99 1)). See).
  • histamine H 3 receptor antagonist or inversagonist thioperamide or GT-233 1 reduces affective seizures and sleep in Narcolepsis dogs (eg, brain Search (see B rain Research), 7 9 3, 2 7 9 '(1 9 8 8)).
  • H 3 receptor is involved in the regulation of wakefulness and sleep and diseases associated with sleep disorders, and selective histamine H 3 agonists, antagonists or inverse agonists are associated with sleep disorders, sleep Diseases with disabilities (eg idiopathic hypersomnia, recurrent hypersomnia, true hypersomnia, narcolepsy, sleep limb movement disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, It is useful for the prevention or treatment of REM sleep disorders, elderly insomnia, 'night sleep worker hygiene, idiopathic insomnia, recurrent insomnia, true insomnia, depression, anxiety, schizophrenia) To suggest. Therefore, the compound or salt described in (1) that acts as a histamine H 3 receptor antagonist or inverse agonist is considered to be effective for the prevention or treatment of sleep disorders and various diseases associated therewith.
  • sleep Diseases with disabilities eg idiopathic hypersomnia, recurrent hypersomnia, true hypersomnia, narcolepsy, sleep limb movement disorder, sleep apn
  • thioperamide or GT-2 3 3 1 improves learning disabilities (LD), attention deficit / hyperactivity disorder (ADHD) -like symptoms (eg, life science (Life Science), 6 9 pp. 4 6 9 (2001)). Furthermore, in rats, (R) — ( ⁇ ) monomethylhistamine reduces objective recognition and learning effects in objective recognition tests and passive evacuation tests.
  • LD learning disabilities
  • ADHD attention deficit / hyperactivity disorder
  • ⁇ monomethylhistamine
  • thioperamide reduces the amnesia caused by the drug in a dose-dependent manner in the scopolamine-induced amnesia test (eg, pharmacology 'Biochemistry' and 'Behavior'). , 6 8 ⁇ , 7 3 5 (200 1)).
  • histamine H3 receptor antagonist or inverse agonist can prevent memory / learning disorders and various diseases (eg, Alzheimer's disease, Parkinson's disease, attention deficit / hyperactivity disorder) Suggests useful treatment. Therefore, the compound or salt of the present invention is considered to be effective for the prevention or treatment of such memory / learning disorders and various diseases associated therewith.
  • thioperamide suppresses feeding behavior in a dose-dependent manner, while promoting the release of histamine in the brain (for example, Behavioral Brain R esearch), 1 04 ⁇ , 14 p. 7 (1 9 9 9)).
  • the histamine H 3 receptor is involved in the regulation of feeding behavior, and the histamine H 3 antagonist or invasagonis ⁇ is an eating disorder ⁇ obesity ⁇ diabetes ⁇ skinny ⁇ 'hyperlipidemia Metabolism system such as illness (metabolic) It is suggested to be useful for prevention or treatment of diseases. Therefore, the compound of the present invention or a salt thereof is considered to be effective for the prevention or treatment of such metabolic diseases.
  • “Also, in rats, (R) — ( ⁇ ) — methylhistamine reduces basal diastolic blood pressure in a dose-dependent manner, and these effects are antagonized by thioperamide (eg, eurobian). See 'Journal' Ob 'pharmacology (European Journal of Pharmacology) 2 ⁇ , 1 29 (1 9 9 3)).
  • histamine H 3 receptor is involved in the regulation of blood pressure, heart rate, and cardiovascular output, and histamine H3 receptor agonist, antagonist or inverse vastonis is associated with high blood pressure, various heart diseases, etc. It is useful for the prevention or treatment of other cardiovascular diseases. Therefore, the compound of the present invention or a salt thereof is considered to be effective for the prevention or treatment of such cardiovascular diseases.
  • thioperamide has been shown to dose-dependently suppress convulsions induced by electrical shock or epileptiform seizures induced by pentylenetetrazole (PTZ) (eg, the Eurobian journal).
  • PTZ pentylenetetrazole
  • 'European J ournal of Pharmacology', 2 34 ⁇ , 1 2 0 (1 9 9 3) and Huo's McCoroji 'By Okemistry' and 'Behavior Pharmacology, Biotech istry and Behavior
  • histamine H 3 receptor antagonist or inverse vaginosis is useful for the prevention or treatment of epilepsy or central convulsions. Therefore, the compound of the present invention or a salt thereof is considered to be effective for the prevention or treatment of such epilepsy or central convulsions.
  • the present invention provides a preventive or therapeutic agent for a metabolic disease, cardiovascular disease or nervous system disease comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Examples of the metabolic disease include at least one selected from the group consisting of obesity, diabetes, hormone secretion abnormality, hyperlipidemia, gout, and fatty liver.
  • Examples of the circulatory disease include at least one selected from the group consisting of angina pectoris, acute congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, and electrolyte abnormality.
  • the above nervous system diseases include sleep disorders, disorders associated with sleep disorders, bulimia, affective disorders, epilepsy, delirium, dementia, attention deficit / hyperactivity disorder, memory disorders, Alzheimer's disease, Parkinson's disease, cognitive impairment, movement disorders And at least one selected from the group consisting of sensory abnormalities, olfactory disturbance, morphine tolerance, drug addiction, alcoholism and tremor.
  • the above nervous system diseases also include idiopathic hypersomnia, recurrent hypersomnia, true hypersomnia, Narcolepsis, sleep limb movement disorder, sleep apnea syndrome, circadian rhythm disorder, chronic At least one selected from the group consisting of fatigue syndrome, REM sleep disorder, insomnia for the elderly, sleep hygiene for night workers, idiopathic insomnia, recurrent insomnia, genuine insomnia, depression, anxiety and schizophrenia It is done.
  • the compound of the present invention or a salt thereof can be used with a concomitant drug. That is, the present invention further prevents or treats a metabolic disease, cardiovascular disease or nervous system disease comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and a concomitant drug as active ingredients. Provide the agent.
  • concomitant drugs include antidiabetic drugs, hyperlipidemia drugs, antihypertensive drugs, and anti-obesity drugs. These concomitant drugs may be used in combination of more than one species.
  • prophylactic or therapeutic agents those containing the following (i), ⁇ (ii) and '(iiii) are provided.
  • aryl group examples include a hydrocarbon ring having 6 to 14 carbon atoms such as a phenyl group, a naphthyl group, a biphenyl group, and an anthryl group.
  • Heteroaryl group means a 5 to 6-membered monocycle having 1 to 4 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or This means a bicyclic heteroaryl group in which a monocyclic heteroaryl group is condensed with a benzene ring or a pyridine ring.
  • a furyl group a enyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, a thiadi'ryl group.
  • “Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group.
  • alkoxy group means a group in which a hydrogen atom of a hydroxy group is substituted with the lower alkyl group, and examples thereof include a methoxy group, an ethoxy group, and a propoxy group.
  • the “cycloalkyl group” preferably represents a cycloalkyl group having 3 to 9 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a cyclononyl group. It is done.
  • the “aralkyl group” means the lower alkyl group having the aryl group, Examples include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 1-naphthylmethyl group, and a 2-naphthylmethyl group.
  • Heteroarylalkyl group means a group in which the heteroaryl group and the alkyl group are bonded, for example, furan-3-ylmethyl group, furan-2-ylmethyl group, furan-3-ylethyl.
  • furan-2-fruethyl group furan-3-ylpropyl group, furan-2-ylpropyl group, thiophene-1-ylmethyl group, thiophene-2- ⁇ -rumethyl group, thiophene-1-ylruetyl group, thiophene group 2-ylethyl group, thiophene-3-ylpropyl group, thiophene-2-ylpropyl group, 1H-pyrrole-3-ylmethyl group, 1H-pyrrole-2_ylmethyl group, 1H-pyrrolenoyl group 3-ylethylyl group, 1 H-pyrrole-2-ylethyl group, 1 H-pyrrole-3 f-
  • Halogen atom means, for example, fluorine atom, chlorine atom, bromine atom, iodine atom and the like.
  • X, Y, ⁇ and W each independently represent a methine group or an S element atom which may have a substituent selected from the group consisting of the substituent group ⁇ .
  • Specific examples include those in which 1 or 2 of X, 1, ⁇ and W is a nitrogen atom, particularly .1 is a nitrogen atom.
  • X, ⁇ and W are methine groups which may have a substituent, ⁇ is a nitrogen atom, X, ⁇ and W are methine groups which may have a substituent, and ⁇ is , Nitrogen atom, X, ⁇ and ⁇ are methine groups optionally having a substituent, W is exemplified by nitrogen atom, and more preferably,
  • X, ⁇ and ⁇ are methine groups which may have a substituent
  • W is a nitrogen atom
  • X, ⁇ and W are methine groups which may have a substituent
  • ⁇ is A nitrogen atom is recommended.
  • a methine group optionally having a substituent selected from the group consisting of substituent groups refers to an unsubstituted methine group, or a substituent selected from the group consisting of substituent group ⁇ Means a methine group having a group, and the substituent can be selected from the group consisting of the substituent group ⁇ .
  • Substituent group ⁇ is a halogen atom, a hydroxy group, a lower alkyl group (this group may be substituted with a hydrogen atom, a hydroxy atom, a hydroxy group or an alkoxy group), a cycloalkyl group (the group is A halogen atom, which may be substituted with a hydroxy group or an alkoxy group, an alkoxy group (the group may be substituted with a cycloalkyl group, a halogen atom or a hydroxy group), a cycloalkoxy group (the cycloalkoxy group).
  • One of the carbon atoms constituting the Si group may be substituted with a nitrogen atom, or the nitrogen atom may be substituted with an alkanoyl group), an amino group, a cyano group, a mono- or di-lower alkyl.
  • Amino group formyl group, alkanoyl group, mono or Di-lower alkyl group rubermoyl group, aryl carbamoinole group, heteroaryl group norberamoyl group, 'aryl alkyl group rubamoyl group, heteroaryl alkylcarbamoyl group, lower alkylsulfonyl group, lower alkylthio group, aryloxy carboluminol group, Aryloxycarbonylcarbonylamino group, aralkoxycarbonylcarbonylamino group, alkanoylamino group, allylcarbonylamino group, arylalkylcarbonyl group, lower alkylsulfonylamino group, arylsulfonylsulfonylamino group, lower alkylsulfuric group It is selected from the group consisting of a famoyl group, an arylsulfamoyl group, an aryl
  • halogen atom for the substituent examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • Examples of the lower alkyl group for the substituent include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.
  • the lower alkyl group may be substituted with a halogen atom, a hydroxyl group or an alkoxy group.
  • Examples of the lower alkyl group substituted with a halogen atom include a fluoromethyl group, a chloromethyl group, a 2-fluoroethyl group, and a 2-chloroethyl group.
  • Examples of the lower alkyl group substituted with a hydroxy group include a hydroxymethyl group and a 2-hydroxyxetyl group.
  • Examples of the cycloalkyl group for the substituent include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
  • cycloalkyl group may be substituted with a halogen atom, a hydroxyl group or an alkoxy group.
  • alkoxy group for the substituent examples include a methoxy group, an ethoxy group, and an isopoxy group.
  • alkoxy group may be substituted with a halogen atom or a hydroxyl group.
  • the cycloalkyloxy group of the substituent means a group in which the cycloalkyl group and an oxygen atom are bonded. Specifically, for example, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, Examples thereof include a cyclohexyloxy group.
  • One of the carbon atoms constituting the cycloalkyloxy group is a nitrogen atom. May be replaced.
  • the group in which one of the carbon atoms constituting the cyclyl alkyloxy group is substituted with a nitrogen atom is preferably a 4- to 7-membered aliphatic ring.
  • an azetidine-3-yloxy group Pyrrolidine-3-yloxy group, piperidine-4-yloxy group, homopiperidine-4-yloxy group and the like.
  • the nitrogen atom in the 4- to 7-membered nitrogen-containing aliphatic ring may be substituted with an alkanol group, a lower alkylsulfonyl group, a diphenylmethyl group, a honolemil group, or a lower alkoxy group.
  • Examples of the lower alkanol group include a acetyl group and a propionyl group.
  • the lower alkylsulfonyl group means a group in which a lower alkyl group as defined above and a sulfonyl group are bonded. Specifically, for example, a methylsulfonyl group, an ethylsulfonyl group, an isopropylsulfonyl group, a propylsulfonyl group, a butylsulfo group, and the like. Nyl group etc. are mentioned. .
  • the lower alkoxycarbonyl group means a group in which the lower alkoxy group and a carbonyl group are bonded. Specific examples include a methoxycarbonyl group, an ethoxy ′ carbonyl group, and an isopropyloxycarbonyl group. .
  • the mono-lower alkylamino group of the substituent means an amino group mono-substituted by the lower alkyl group, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, sec-butylamino group. Or a tert- butylamino group etc. are mentioned. .
  • the di-lower alkylamino group of the substituent means an amino group which can be di-substituted by the same or different lower alkyl group, for example, a dimethylamino group, a jetyl amino group, a dipropylamino group, a methylpropylamino group or diisopropyl. Examples include amino groups.
  • the alkyl group of the substituent means a group in which the alkyl group and the carbonyl group are bonded, and examples thereof include a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, and an isopropylcarbonyl group.
  • the mono-lower alkyl strength rubamoyl group of the substituent means a strength rubamoyl group mono-substituted with the lower alkyl group. Examples thereof include butyl carbamoyl group, sec-butyl carbamoino group, tert-butyl carbamoino group and the like.
  • the di-lower alkyl strength rubamoyl group of the substituent means a strength rubamoyl group di-substituted with the same or different lower alkyl group, for example, a dimethylcarbamoyl group, a jetylcarbamoyl group, an ethylmethylcarbazol group. Group, dipropyl-powered rubermoyl group, methylpropyl-powered rubermoyl group, diisopropyl-powered rubermoyl group and the like. '
  • the aryl group rubermoyl group of the substituent means a group to which one or two of the above-mentioned “aryl groups”, such as a phenyl carbamoyl group, naphthalene 1-inorecanolevermoyl, is bonded. Group, naphthalene-2-ylcarbamoyl group and the like. ''.
  • the heteroaryl force ruberamoyl group of the substituent means a group in which 1 or 2 said “heteroaryl group” and force ruberamoyl group are bonded, for example, furan 2 f force ruberamoyl group, furan 3-ylcarbamoyl group, thiophene 1.2-isolecarbamoyl group, thiophene 3-ylcarbamoinole group, 1 H-pyrrole 2-ruinol force rubamoyl group, 1 H-pyrroloinol group 3-inole power Rubamoyl group, 1 H—imidazole 2-ylcarbamoyl group, 1 H—imidazole 4-ylcarbamoyl group, 3 H—imidazole 4-ynolecanolemoyl group, 4 H— [1, 3, 4 ] Triazole 1-ylcarbamoyl group, 2 H— [1, 2, 4] Triazole 1 3- ⁇ f Nore force rub
  • the arylalkyl-powered rubermoyl group of the substituent means a group in which 1 or 2 of the above-mentioned “aralkyl group” and the powered rubermoyl group are bonded, for example, a benzylcarbamoyl group, 1-phenol. Rutilecarbamoyl group, 2-phenyl earthylcarbamoyl group.
  • heteroarylalkyl group rubamoyl group of the substituent means a group in which one or two “heteroarylalkyl groups” and a group of rubamoyl groups are bonded, for example, a furan-1-inoleylmethylcarbamoyl group.
  • the lower alkylthio group of the substituent means a group in which the lower alkyl group and a sulfur atom are bonded, and examples thereof include a methylthio group, an ethylthio group, a proprthio group, and an isopropylthio group.
  • the aryloxy group of the substituent means a group in which the aryl group and an oxygen atom are bonded, and examples thereof include a phenoxy group, a naphthalene-1-yloxy group, and a naphthalene-2-yloxy group.
  • the aryloxycarbonylamino group of the substituent means a group in which the aryloxy group and the carbonylamino group are bonded, and examples thereof include a phenoxycarbonylamino group.
  • arylalkyloxycarbonylamino group of the substituent for example, N-dioxycarbonylamino group, 1-phenylethyloxycarbonylamino group, 2-phenethylethyloxycarbonylamino group, 1-naphthylmethyloxycarbonylamino group, 2-naphthylmethyloxycarbonyl group An amino group etc. are mentioned. .
  • the alkoxycarbonylamino group of the substituent means a group in which the alkoxy group and the carbonylamino group are bonded.
  • a methoxycarbonylamino group, a toxoxycarbonylamino group, a propoxycarbonylamino group, etc. Is mentioned.
  • the alkanoylamino group of the substituent means a group in which the alkanoyl group and an amino group are bonded.
  • a methylcarbonylamino group, an ethylcarbonylamino group, a propylcarbonylamino group examples thereof include an isopropylcarbolamino group and an isobutylcarbonylamino group.
  • the arylarylcarbonylamino group of the substituent means a group in which the aryl group and the carbonylamino group are bonded, and examples thereof include a phenylcarbonylamino group, a naphthalene 1-ylcarbonylamino group, Naphthalene 2- ⁇ -fcarbonylcarbonylamino group and the like.
  • the arylalkylcarbonyl group of the substituent means a group in which the aralkyl group and the carbonyl group are bonded to each other.
  • a benzylcarbonyl group a naphthalene 1-inolecarbonyl group, a naphthalene 1- ⁇ f And a rucarbonyl group.
  • the lower alkylsulfonylamino group of the substituent means a group in which the lower alkyl group and a sulfonylamino group are bonded to each other, and examples thereof include a methylsulfonylamino group, an ethylsulfonylamino group, and an isopropylsulfonylamino group. And n-butylsulphonylamino group.
  • the arylsulfonylamino group of the substituent means a group in which the aryl group and the sulfonylamino group are bonded, for example, a phenylsulfonylamino group, a naphthalene 1-1 And a rusulfonylamino group, a naphthalene-2-ylsulfoninoreamino group, and the like.
  • the lower alkyl sulfamoyl group of the substituent means a group in which 1 or 2 of the above “alkylamino group” and a sulfonyl group are bonded, and examples thereof include a methylsulfamoino group, an ethylsulfamoyl group, Examples thereof include propylsulfamoyl group, isopropinolesnorefamoyl group, dimethinolesnolefamoyl group, jetylsulfamoyl group, ethylmethylsulfamoyl group, and isopropylmethylsulfamoyl group.
  • the arylsulfamoyl group of the substituent means a group in which the aryl group and an aminosulfonyl group are bonded, for example, a phenylsulfamoyl group, naphthalene. And 1-1ylsulfamoyl group and naphthalene-2-ylsulfamoyl group.
  • Examples of the aryl group for the substituent include the same groups as the aryl group.
  • Examples of the heteroaryl group for the substituent include the same groups as those described above.
  • Examples of the aralkyl group for the substituent include the same groups as the aralkyl group.
  • the aralkyloxy group of the substituent means a group bonded to the aralkyl group and an oxygen atom.
  • a halogeni atom, a hydroxy group, a lower alkyl group (the group may be substituted with a halogen atom, a hydroxy group or an alkoxy group), a cycloalkyl group (the group is , A halogen atom, a hydroxy group or an alkoxy group may be substituted), an alkoxy group, a cycloalkoxy group (one of carbons constituting the cycloalkoxy group may be substituted with a nitrogen atom, or The nitrogen atom may be substituted with an alkanoyl group), a cyano group, an alkanoyl group, a lower alkylsulfonyl group, a lower alkylthio group, an aryl group, an aryloxy group or a heteroaryl group, particularly a halogen atom, A droxy group, a lower alkyl group (the group is a halogen atom, a hydroxy group or
  • ⁇ represents one (C (R 3 ) (R 4 )) ml —, — C (O) —, one O— or — N (R 5 ) —.
  • Scales 3 and 1 and 4 each independently represent a hydrogen atom ′, a hydroxyl group, a lower puralkyl group, an aralkyl group, or an aryl group.
  • m 1 represents 0 or 1.
  • R 5 represents a hydrogen atom, a lower alkyl group, an aralkyl group or an aryl group.
  • one (C (R 3 ) (R 4 )) ml — indicated by A specifically, for example, a single bond, a methylene group, one CH (CH 3 ) ⁇ , -C (CH 3 ) 2 — Of these, a single bond, a methylene group, and the like are preferable.
  • One N (R 5 ) represented by A includes, for example, one NH—, methylamino group, ethylamino group, isopropylamino group, etc. Among these, one NH—, methylamino group, ethylamino group, etc. Is preferred.
  • B represents one N (SO R 1 ) —, one N (COR 2 ) one, one N (R 50 ) —, one O— or —C (O) one.
  • R 1 and R 2 are each independently a hydrogen atom, a lower alkyl group, an aralkyl Indicates a group or aryl group.
  • R 5 ° represents a hydrogen atom or a lower alkyl group.
  • One N (S 0 2 R — represented by B includes, for example, a methanesulfonylamino group, an ethanesulfonylamino group, an isopropylsulfonylamino group, a benzylsulfonylamino group, a phenylsulfonylamino group, and the like. Of these, methansulfonylamino groups and ethanesulfonylamino groups are preferred.
  • Examples of 1 N (COR 2 ) — represented by B include a methylcarbonylamino group, an ethylcarbonylamino group, an isopropylcarbonylamino group, a phenylcarbonylamino group, a benzylcarbonylamido group, and the like. Of these, methylcarbonylamino group, ethylcarbonylamino group, etc. are preferred.
  • Examples of 1 N (R 50 ) — represented by B include 1 NH—, methylamino group, ethylamino group, isopropylamino group, benzylsulfonylamino group, phenylsulfonylamino group, and the like.
  • An NH—, methylamino group, and ethylamino group are preferred.
  • D represents one (C (R 30 ) (R 40 )) m2 —, ten thousand, one N (R 51 ) one or one C (O) —.
  • ⁇ 4 are each independently a hydrogen atom, a hydroxyl group, a lower alkyl group; an aralkyl group or an aryl group., M2 represents 0 or 1;
  • R 51 represents a hydrogen atom or a lower alkyl group.
  • Examples of one represented by D (C (R 30 ) (R 40 ).) M2 — include, for example, a single bond, a methylene group, one CH (CH 3 ) —, one C (CH 3 ) 2 —, and the like. .
  • Examples of 1 N (R 51 ) — represented by D include 1 NH—, a methylamino group, an ethylamino group, and an isopropylamino group. Among these, 1 NH—, a methylamino group, and an ethylamino group are preferable.
  • Q represents a methine group or a nitrogen atom.
  • R is the formula (I I)
  • any hydrogen atom in the formula (II) is a lower alkyl group (the lower alkyl group may be substituted with a halogen atom, an oxo group or an alkoxy group), a cycloanolalkyl group, a hydroxy group, an alkoxy group. (The alkoxy group may be substituted with a halogen atom) and a substituent selected from the group consisting of halogen atoms.
  • R 6 represents a hydrogen atom or a lower alkyl group, and among them, a lower alkyl group is preferable.
  • Measure 7 and! 3 ⁇ 4 8 each independently represent a lower alkyl group, a cycloalkyl group, an aralkyl group, a heteroaryl alkyl group, or R 7 , R 8 and the nitrogen atom to which they are bonded together. Therefore, a 4- to 8-membered nitrogen-containing aliphatic heterocyclic group is formed. R 7 is also 4 to 4 together with C a and the nitrogen atom to which they are bonded.
  • An 8-membered nitrogen-containing aliphatic heterocyclic group may be formed.
  • Examples of the 4- to 8-membered nitrogen-containing aliphatic heterocyclic group include azetidinyl group, pyrrolidinyl group, piperidinyl group, homopiperidinyl group, morpholino group and the like.
  • Examples of the group represented by the formula (I 1— 1) include the following formula (I 1 _ 1 1 1) "
  • Examples of the group represented by the formula (I 1-2) include a formula (I 1-2—
  • Examples of the group represented by the formula (II 1 3) include, for example, the formula (II 1 3-1)
  • Examples of the group represented by the formula (I 1-4) include a formula (I 1 -4- 1)
  • a group represented by (11-4-2) is preferred.
  • Examples of the group represented by the formula (II 1-5) include, for example, the formula (I 1-5-1)
  • N-Methyl-7'-oxo1N- (.2-Piperidine 1-ylethyl) 1-7 1 H-spiro [cyclohexane-1,5'-furo [3,4-b] pyridine] 1 4-carboxami De,.
  • the compound represented by the compound (I-1) according to the present invention or a pharmaceutically acceptable salt thereof can be produced, for example, by the following method.
  • Ha 1 represents a halogen atom
  • 1 ⁇ means a methanesulfol group, a trifluoromethanesulfonyl group, a para-toluenesulfonyl group, etc., and other symbols are the same as above]
  • This step is a method for producing a compound (2) by reacting a compound (1) with 1,4-cigrohexanedione-monoethylene monoketal in the presence of a base.
  • the compound (1) used in this reaction is produced by a method described in the literature (for example, WO O 3/0 1 408 3 etc.), a method according to this, or a combination thereof with a conventional method. be able to.
  • Specific examples of compounds (1) include, for example, 3-bromo-1,4-pyridinecarboxylic acid, 3-bromo-2-pyridinecarboxylic acid, 2-fluoro-3-chloro-1,4-pyridine. A carboxylic acid etc. are mentioned.
  • the amount of 1,4-cyclohexanedione monomonoethylene monoketal is usually 1 to 5 equivalents, preferably 1 to 2 equivalents per 1 equivalent of the compound (1).
  • Examples of the base to be used include butyl lithium, lithium 2, 2, 6, 6-tetramethylpiperidide and the like.
  • the amount of the base is usually 2 to 10 equivalents, preferably 2 to 4 equivalents, relative to 1 equivalent of the compound (1).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
  • examples thereof include tetrahydrofuran (hereinafter abbreviated as “THF”), jetyl ether, tert-butyl methyl ether, and the like. THF is preferred.
  • the reaction temperature is usually ⁇ 100 ° C. to .100 ° C., preferably 1 78 ° C. to 50 °.
  • the reaction time is usually 1 hour to 48 hours, preferably 1 hour to 24 hours.
  • the compound (2) thus obtained can be isolated or purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. or without isolation and purification. It can be attached to the next process.
  • This step is a method for producing the compound (3) by removing the ketal group of the compound (2).
  • the removal of the ketal group can be achieved by a method described in the literature (for example, Protective Groupsin Organic Synthesis, Ding. W. Green, 2nd edition, John W ile y & S ons, 1 9 9 1 year, etc.) It can be carried out by a method, a method according to this method, or a combination of these and a conventional method.
  • the acetal group can be removed using an acid such as hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, trifluoroacetic acid or the like.
  • an acid such as hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, trifluoroacetic acid or the like.
  • the amount of acid used is usually 0.1 to 100 equivalents, preferably 0.5 to 50 equivalents, relative to 1 equivalent of compound (2).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
  • examples thereof include water and water-containing methanol, ethanol, acetone, THF, 1,4-dioxane, acetic acid, and the like. Of these, methanol, ethanol, acetone, THF, and 1,4-dioxane are preferred. '
  • the reaction temperature is usually 0 ° C to 200 ° C, preferably 20 ° C to 150 ° C.
  • the reaction time is usually 1 hour to 48 hours, preferably 1 hour to 10 hours.
  • the compound (3) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. or without isolation and purification. It can be attached to the next process.
  • This step is a method for producing the compound (4) by subjecting the carbonyl group of the compound (3) to a reduction reaction.
  • Examples of the reducing agent include sodium borohydride, lithium lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, tri (tert-butoxy) aluminum lithium hydride, and the like.
  • the amount of the reducing agent is usually 1 to 20 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (3).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
  • THF THF-water mixed solvent
  • 1,4-dioxane 1,4-dioxane water mixed solvent
  • methanol ethanol
  • ethanol examples thereof include jetyl ether, methylene chloride and the like.
  • a mixed solvent of THF and THF-water is preferable.
  • the reaction temperature is usually from 100 ° C to 100 ° C, preferably —100 ° C to 50 ° C.
  • the reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 4 hours.
  • the compound (4) thus obtained can be obtained by known separation and purification means such as concentration, It can be isolated and purified by vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, etc., or can be used in the next step without isolation and purification.
  • This step is a method for producing the compound (5) by reacting the compound (4) with the compound Lt 1 C 1 in the presence of a base.
  • the base include triethylamine, sodium carbonate, potassium carbonate, diisopropylethylamine, pyridine and the like. Among these, triethylamine, diisopropylethylamine and the like are preferable.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (4). ''
  • Examples of the compound I ⁇ —C 1 include methanesulfuric mouthlid, trifluoromethanes / rephonino chloride, noratorenens norehonino chloride, and benzeneshonhonhon chloride. Of these, methanesulfonyl chloride, para-enesulfonyl chloride and the like are preferable.
  • the amount of L 1 C 1 is usually about 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (4).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
  • THF methylene chloride, black mouth form are preferred.
  • the reaction temperature is usually 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time is usually 5 minutes to 12 hours, preferably 5 minutes to 4 hours.
  • the compound (5) thus obtained can be isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.
  • This step is a method for producing a compound (6) by reacting a compound (5) with a cyano compound.
  • the cyan compound examples include tetraethylammonium cyanide, tetraptylammonium cyanide, sodium cyanide, potassium cyanide, and the like. Among these, tetraethylammonium cyanide Tetrabutylammonium cyanide is preferred.
  • the amount of the cyan compound is usually 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (5).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction. Examples thereof include N, N-dimethylformamide (hereinafter referred to as “DMFJ”), THF, dimethylsulfoxide, and acetonitrile. Of these, DMF is preferred.
  • the reaction temperature is usually 0 ° C. to 150 ° C., and preferably 50 ° C. to 10 ° C.
  • the reaction time is usually 1 hour to 48 ° C. Hours, preferably 1 to 24 hours.
  • the compound (6) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like. It can be attached to the next process.
  • This step is a method for producing the compound (7) by hydrolyzing the compound (6) in the presence of an acid.
  • Examples of the acid used include sulfuric acid and hydrochloric acid.
  • the amount of the acid is 1 to 100 equivalents, preferably 1 to 50 equivalents, relative to 1 equivalent of the compound (6).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include 1,4-dioxane and water.
  • the reaction temperature is usually 20 ° C to 200 ° C, preferably 50 ° C to 150 ° C.
  • the reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.
  • the compound (7) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process without any problems.
  • Compound (7) can also be produced by methods described in the literature (for example, WO 03 014083).
  • This step comprises reacting compound (7) with compound (IV-1), (IV-2), (IV-3), (IV-4) or (IV-5).
  • This is a method of manufacturing (1-1).
  • This reaction is described in the literature (eg, peptide synthesis basics and experiments, Nobuo Izumiya et al., Maruzen, 1980, Comprehensive Organic Synthesis, Vol. 6, P erg am on Press, 1999, etc.), a method according to it, or a combination thereof with a conventional method may be used to carry out a normal amide formation reaction, that is, the ability to perform using a condensing agent well known to those skilled in the art.
  • Examples of the base used include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1,8-diazabisic Mouth [5. 4. 0] Third-class aliphatic amines such as Wunde 7-Yen (DBU), 1, 5-azabicyclo [4 ⁇ 3.0] Nona 5-Yen (DBN); Aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline, etc.
  • DBU Wunde 7-Yen
  • DBN Nona 5-Yen
  • Aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline, etc.
  • N-hydroxybenzotriazole water Japanese, N-Hydroxysuccinimide, N-Hydroxy-5-Nonolebornene 1 2 3-Dicarboxyimide or 3-Hydroxy 3 4-Dihydro 4-Oxo 1, 2, 3, benzotriazole, etc. Among them, N-hydroxybenzotriazole and the like are preferable. .
  • the amount of compound (IV 1) (IV-2) (IV-3) (IV-4) or (IV-5) used is usually based on 1 equivalent of carboxylic acid derivative (7) or its reactive derivative. 0.1 to 10 equivalents, preferably 0.5 to 3 equivalents.
  • the compound (IV-1) means the above-mentioned (I I 1) amino compound, and specifically, for example, the above-mentioned ((I I-1)) amino compound.
  • the compound (I V-2) means the corresponding (I I-12) amino compound, specifically, for example, the (I I-12-1) corresponding amino compound.
  • Compound (IV-3) means the corresponding amino compound (I I-13), and specific examples include (I I-3-1) the corresponding amino compound.
  • the compound (IV-4) means the corresponding amino compound (I I-4), and specifically includes, for example, the corresponding amino compound (I I-4-1).
  • the compound (I V-5) means the above-mentioned amino compound corresponding to (I I-5), and specifically includes, for example, the above-mentioned amino compound corresponding to (I I-5-1). '
  • the amount of the amide-forming reagent varies depending on the type of compound and solvent used and other reaction conditions, but usually 1 to 10 equivalents per 1 equivalent of the carboxylic acid compound (7) or its reactive derivative, Preferably 1 to 3 equivalents.
  • the amount of the condensation aid varies depending on the compound used, the type of solvent and other reaction conditions, but is usually 1 to 10 equivalents, preferably 1 to 3 to 1 equivalent of the carboxylic acid compound (7) or its reactive derivative. Is equivalent.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 5 equivalents.
  • reaction solvent examples include an inert solvent, and are not particularly limited as long as the reaction is not hindered.
  • methylene chloride, chloroform, 1,2-dichloroethane, DMF, ethyl acetate, Acetic acid methyl ester, acetonitrile, benzene, xylene, toluene, 14_dioxane, THF, dimeth Xetane or a mixed solvent thereof may be mentioned, but from the viewpoint of securing a suitable reaction temperature, for example, methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile or DMF is preferred.
  • the reaction temperature is usually from 1 78 ° C to the boiling point of the solvent, preferably 0 to 30 ° C. .
  • the reaction time is usually 0.5 to 96 hours, preferably 3 to 24 hours.
  • the base, amide-forming reagent, and condensation aid used in this step can be used alone or in combination.
  • the compound (I-11) according to the present invention is isolated and purified by known separation and purification means, for example, concentration, pressure concentration, crystallization, solvent extraction, reprecipitation, chromatography, etc. You can do it.
  • the compound (1-2) according to the present invention can be produced by the following method.
  • compound (8) is reacted with 11-dimethyl-2-hydroxytylamine in the presence of a base to produce compound (9).
  • Examples of the base include triethylamine, trimethylamine, NN-dipropylethylamine, N-methylmorpholine, pyridine and the like. Among these, ⁇ -ethylamine, NN-diisopropylethylamine, pyridine Etc. are preferred.
  • the amount of the base is usually 1 to 10 equivalents per 1 equivalent of the compound (8),
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 to 50 ° C. It is.
  • the reaction time is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
  • the reaction solvent may be any one that does not interfere with the reaction, and if it is anything, specifically, for example, black mouth form, methylene chloride, 1,2-dichloroethane, THF, ethyl acetate, Examples include acetonitrile, 1,4-dioxane, toluene, dimethoxetane, and the like. Preferred is chloroformate, methylene chloride, THF, and the like.
  • the compound (9) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be used in the next step without purification.
  • This step is a method for producing the compound (1 Q) by reacting the compound (9) with thionyl chloride.
  • sulfuryl chloride phosphorus oxychloride or the like may be used instead of chloride.
  • the amount of thionyl chloride used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (9).
  • the reaction temperature is usually 0 ° C to 100 ° C, preferably 0 to 50 °.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • reaction solvent Any reaction solvent may be used as long as it does not interfere with the reaction.
  • examples thereof include benzene, methylene chloride, 1, .2-dichloroethane and the like.
  • the compound (10) thus obtained is isolated and purified or isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, medium extraction, reprecipitation, chromatography, etc. It can attach to the next process without it.
  • This step is a method for producing a compound (1 1) by reacting the compound (10) with 1,4-cyclohexanedione-monoethylene monoketal in the presence of a base.
  • a base examples include butyl lithium and lithium 2, 2, 6, 6-tetramethylbiperidide, and butyl lithium is preferable.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 equivalent to 1 equivalent of the compound (10). Is 1 to 3 equivalents
  • the amount of 1,4-cyclohexanedione monomonoethylene ketal is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (10). .
  • the reaction temperature is usually from 78 ° C to 100 ° C, preferably _78 ° C to 5 ° C.
  • the reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 12 hours.
  • reaction solvent Any reaction solvent may be used as long as it does not interfere with the reaction.
  • examples thereof include THF, jetyl ether, tert-butylmethyl ether, etc. Among these, THF is preferable. .
  • the ichigo compound (11) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, etc. It can be used in the next step without isolation and purification.
  • This step is a method for producing compound (12) by reacting compound (11) with an acid.
  • Examples of the acid include sulfuric acid, hydrochloric acid, para-toluenesulfonic acid, trifluoroacetic acid and the like.
  • the amount of the acid is usually 0.1 to 1000 equivalents, preferably 0.1 to 10 equivalents, relative to 1 equivalent of the compound (11).
  • the reaction temperature is usually 0 ° C to 200 ° C, preferably 20 ° C to 100 ° C.
  • the reaction time is usually 1 hour to 72 hours, preferably 1 hour to 48 hours.
  • the reaction solvent may be any solvent as long as it does not interfere with the reaction. Examples thereof include water, acetone, THF, 1,4-dioxane, etc. Among these, acetone, THF, etc. Is preferred.
  • the ICH compound (12) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. Or it can attach to the next process, without isolating and purifying.
  • compound (1 3) is produced by subjecting compound (1 2) to a reduction reaction. It is a method to build. _
  • reaction in this step can be carried out by the same method as in Step 3, a method analogous thereto, or a combination of these with a conventional method.
  • the compound (1.3) thus obtained is isolated and purified or isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can attach to the next process without it.
  • This step is a method for producing a compound (14) by reacting the compound (1 3) with the compound 1 C 1 in the presence of a base. .
  • reaction in this step can be carried out by the same method as in Step 4, a method analogous thereto, or a combination of these with conventional methods.
  • the compound (14) thus obtained is isolated and purified or isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can attach to the next process without it.
  • This step is a method for producing compound (15) by reacting compound (14) with a cyano compound.
  • reaction in this step can be carried out by the same method as in Step 5, a method analogous thereto, or a combination of these with conventional methods.
  • the compound (15) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can attach to the next process, without doing.
  • This step is a method for producing the compound (16) by hydrolyzing the compound (15).
  • reaction in this step can be carried out by the same method as in Step 6, a method analogous thereto, or a combination of these with conventional methods.
  • the compound (16) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can attach to the next process, without doing.
  • This step is carried out by reacting the compound (16) with the compound (IV-1), (IV-2), (IV-3), (IV-4) or (IV-5).
  • Change This is a method for producing a compound (I 1 2).
  • reaction in this step can be carried out by the same method as in Step 7, a method analogous thereto, or a combination of these with conventional methods.
  • Compounds (IV-1) include, for example, N-methyl-1-N- (piberidinoethylol) amine, N-methyl-N- (pyrrolidinoethyl) amine, 1- (2-aminoethyl) piperidine, 1- (2_Aminoethyl) pyrrolidine, N, N, ⁇ '-trimethylenoethylenediamine, ⁇ -cyclohexenoyl ⁇ , ⁇ ' -dimethylenoethylenediamine or ⁇ -ethyloylamine (piperidinoethyl) amine Etc.
  • Compound (IV-2) includes, for example, '(S)-1-(2-pyrrolidinylmethyl) pyrrolidine, (S) — 1- (2-pyrrolidinylmethyl) piperidine, ( S) -1-(2-piperidinylmethyl) piperidine or) 1-1- (2-piperidinylmethyl) .pyrrolidine and the like.
  • Examples of compounds (IV-3) include 1-methylbiperazine, 1_isobutinorepiperazine, 1-cyclopentylbiperazine (R) —octahydride, pyropyro [1, 2-a] birazine or 1 -Ethyl (3 S) -Methylbiperazine and the like.
  • Examples of the compound (IV-4) include N- (1-cyclopentyl-3-pyrrolidinyl) 1-N-methylamine or N- (1-1-isobutyl-1-3-pyrrolidinyl) 1-N-methylamine. It is done.
  • Examples of the compound (IV-5) include 1- (1-isopropylpyrrolidine-1-yl) 1-N-methyl-1-methanamine and the like.
  • the thus obtained compound (I-12) according to the present invention is isolated by a known separation and purification method, for example, concentration, concentration under pressure, solvent extraction, crystallization, reprecipitation, chromatography, etc. Can be purified.
  • the compound (I-3), (I-14) or (I-15) according to the present invention can be produced, for example, by the following method.
  • R 61 represents a lower alkyl group, 'H a 1 represents a halogen atom, and other symbols are the same as above]
  • sodium hydride for example, sodium hydride, strong lithium hydride, calcium hydride, butyl lithium and the like can be mentioned. Of these, sodium hydride is preferred.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents per 1 equivalent of the compound (1-1-1), (1-1-2) or (1-1-3). is there.
  • the compound (17) include, for example, iodinated acetyl, methyl iodide, methyl trifluoromethyl sulfonate, methyl methyl sulfonate, methinorepara toluene sulfonate, methyl bromide, and bromide til. .
  • the amount of the compound (1 7) is usually 1 to 10 equivalents, preferably 1 to 1 with respect to 1 equivalent of the compound (1-1-1), (I 1-1-2) or (I 1-1-3). 3 equivalents.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include DMF and THF.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 to 50.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • the compound (I-3), (I_4) or (I-5) thus obtained can be obtained by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chroma It can be isolated and purified by topography etc.
  • the compound (I-16) according to the present invention can be produced, for example, by the following method.
  • Pro represents a protecting group for an amino group
  • R 9 represents a hydrogen atom or a lower alkyl group
  • R 1 Represents a hydrogen atom, a lower alkyl group, an aryl group or a heteroaryl group, or R 9 and R 1 .
  • This step is a method for producing compound (19) by reacting compound (7) with compound (18). '
  • This reaction can be carried out in the same manner as in Step 7, a method analogous thereto, or a combination of these with conventional methods.
  • Compounds (18) include, for example, 1-B oc-piperazine, l_B oc-homopiperazine, 1-benzyloxycarbolupiperazine, 1-acetylpiperazine, 1-benzoylbiperazine, 1 _Benzylpiperazine and the like.
  • the compound (19) thus obtained can be isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.
  • This step is a method for producing a compound (20) by removing the amino protecting group of the compound (19).
  • the amino protecting group can be removed by the method described in the above literature (Protective Groups in Organic Synthesis), a method based thereon or a combination thereof with a conventional method. This can be done by combining.
  • the compound (20) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like. The following can be added.
  • This step is a method for producing the compound (I-16) according to the present invention by reacting the compound (20) with the compound (21).
  • the reaction in this step is a so-called reductive alkylation reaction, in which the compound (20) and the compound (2'1) are reacted in the presence of a base and a reducing agent to produce the compound (I-6) according to the present invention.
  • a reductive alkylation reaction in which the compound (20) and the compound (2'1) are reacted in the presence of a base and a reducing agent to produce the compound (I-6) according to the present invention.
  • Examples of the compound (21) include cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone, acetone, 3_pentanone, 2-butanone, 3-methyl-2-butanone, 3 xanone, formaldehyde, phase aldehyde Examples include hydride, propion aldehyde, and isobutyl aldehyde. .
  • the amount of compound (21) is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (20).
  • Examples of the base include triethylamine, 'trimethylamine, N, N-dipropylethylamine, N-methylmorpholine, N-methylolpyrrolidine, N-methylbiperidine, and the like.
  • the amount of the base is usually 0 to 5 equivalents, preferably 0 to 2 equivalents, relative to 1 equivalent of the compound (20).
  • Z n C 1 2 - N a BH 3 CN acetic acid one Na BH 3 CN ⁇ over Na BH (OA c) 3, sodium borohydride and the like, among these, Z n C 1 2 - n a BH 3 CN, one n a BH 3 CN such as acetic acid is preferred.
  • the amount of the reducing agent is usually 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (20).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
  • examples thereof include methanol, ethanol, black mouth form, methylene chloride, THF 1,4-dioxane, etc.
  • methanol, ethanol Methylene chloride is preferred.
  • the reaction temperature is usually 0 ° C to 100 ° C, preferably 0 to 50 ° C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 2 hours. 4 hours.
  • the thus obtained compound (I-16) can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. . .
  • This step is a method for producing the compound (I 1-2-1) according to the present invention by reacting the compound (A) with the compound (2 2) in the presence of a base and a palladium catalyst.
  • Examples of the base include sodium carbonate, cesium carbonate, cesium fluoride, calcium carbonate, sodium hydride, sodium carbonate, carbonated lithium, potassium phosphate, potassium acetate, potassium tert-butoxide, and triethylamine. .
  • the amount of the base to be used is generally 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (A).
  • the palladium catalyst include tetrakis triphenylphosphine paradium, dichlorobistriphenylphosphine palladium, dichloro (1,1′-bis (diphenylphosphino) phenolic) palladium, and palladium acetate. .
  • the amount of the palladium catalyst to be used is generally 0.01 to 10 equivalents, preferably ⁇ 05 to 5 equivalents, relative to 1 equivalent of compound (A).
  • Examples of the compound (A) include the compounds produced in Examples 1, 4, 32 and 33.
  • pyridine _ 3-ylboronic acid, pyridin-4-ylboronic acid, pyrimidine-1-ylboronic acid, 2-methoxypyrimidin-1-5-ylboronic acid, 2-methoxypyridine-1 5 Inoleboronic acid, 2-methinole pyridine-5-ylboronic acid, phenylboronic acid, (1-methyl-1H-virazole_4 / ⁇ ) boronic acid, and the like.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include ethylene glycol dimethyl ether, DMF, toluene, THF, 1,4-dioxane, benzene, acetone, methanol and the like.
  • the reaction temperature is usually from 0 ° C. to the reaction temperature of the solvent, preferably from room temperature to 150 ° C.
  • the reaction time is usually 0.1 hour to 72 hours, preferably 0.5 hour to 12 hours.
  • Compound (I 1-2-1) can also be produced by the following method.
  • This step is a method for producing the compound (I 1-2-1) by reacting the compound (A) with the compound (23) in the presence of lithium chloride and a palladium catalyst.
  • the amount of lithium chloride to be used is generally 0.01 to 10 equivalents, preferably 0.05 to 5 equivalents, relative to 1 equivalent of compound (A).
  • a palladium catalyst for example, tetrakis triphenylphosphine paradi Dichlorobis-triphenylenolephosphine palladium, dichloro (1, 1'-bis (diphenylphosphino) phenol) palladium, palladium acetate, etc.
  • the amount of the palladium catalyst is usually 0.01 to 10 equivalents, preferably 0.05 to 5 equivalents, relative to 1 equivalent of the compound (A).
  • Examples of the compound (23) include 2- (tri-n-butyltin) pyrazine, 2- (tri-n-butyltin) pyridine, and the like.
  • the amount of the compound (23) is usually 0.1 to 5 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of the compound (A).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include DMF, toluene, THF, 1,4-dioxane, benzene, and acetone.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably room temperature to 150 ° C.
  • the reaction time is usually from 0.1 hour to 72 hours, preferably from 0.5 hour to 12 hours.
  • the thus obtained compound (I 1-2-1) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography and the like.
  • E represents a lower alkyl group having 1 to 6 carbon atoms or Ar, and the other symbols are the same as described above] can be produced, for example, by the following method.
  • This step is a method for producing compound (1-2-2) by reacting compound (A) with compound (24) in the presence of a base.
  • a base examples include cesium carbonate, potassium carbonate, sodium carbonate, sodium hydride and the like.
  • the amount of the base to be used is generally 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (A).
  • Examples of the compound (24) include, when E is a lower alkyl group, methanol, ethanol, propanol, butanol and benzyl alcohol, etc., and when E force Ar, phenol, 2-hydride. Examples include roxypyridine and 3-hydroxypyridine.
  • the amount of compound (24). To be used is generally 0.1 to 50 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound and K.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction. Examples thereof include DMF, acetone, 1,4-dioxane, benzene, toluene, N-methyl-2-pyrrolidone, and THF. It is possible.
  • the reaction temperature is usually from 0 ° C. to the reflux temperature of the reaction solvent, preferably from room temperature to 150 ° C.
  • the reaction time is usually from 0.1 hour to 72 hours, preferably from 0.5 hour to 12 hours.
  • the compound (1-2-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • the compound (I 1-2-3) according to the present invention can be produced, for example, by the following method.
  • R 91 and R 92 are the same or different and each represents a hydrogen atom or a lower alkyl group, or R 9 R 92 and the nitrogen atom to which they are bonded together have a substituent.
  • a 4- to 8-membered nitrogen-containing aliphatic ring is formed, and other symbols are the same as above]
  • This step is a method for producing compound (I 1-2-3) by reacting compound (A) with compound (25) in the presence or absence of a base.
  • Examples of the base include potassium carbonate, cesium carbonate, sodium hydride, potassium phosphate, sodium carbonate and the like.
  • the amount used is generally 0.1 to 20 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (A).
  • the amount of compound (25) to be used is generally 0.1 to 50 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (A).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include DMF, N-methylol-2-pyrrolidone, tonoleene, benzene, 1,4-dioxane, THF and the like.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably room temperature to 150 ° C.
  • the reaction time is usually from 0.1 hour to 72 hours, preferably from 0.5 hour to 12 hours.
  • Examples of the compound (25) include dimethylamine and morpholine.
  • the thus obtained compound (I 1-2-3) can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • Step 21, Step 22 and Step 23 are preferably in a position where the nitrogen atom and the carbon atom to which Ha 1 is bonded are adjacent to each other in X and Y.
  • the compounds of the present invention can exist as pharmaceutically acceptable salts, and such salts are represented by the formulas (I-1), ( ⁇ -1), ( ⁇ -1), which are included in the above formulas (I) and (I). i), (1-1-2), (1-1-3), (1-2), (1-21-2), (1-2-2), (1-2-3), 1-3), (1-4), (1-5), (1-6), (1-7), (1-8), (I 1-9) or (I-10) Can be produced according to a conventional method. These compounds can be converted into a pharmaceutically acceptable salt or ester by a conventional method, and conversely, conversion from a salt or ester force to a free compound can also be performed according to a conventional method.
  • the acid addition salt examples include hydrohalide (hydrochloride, hydrofluoride, hydrobromide, hydrobromide, etc.), inorganic acid (nitrate, perchlorate, Sulfuric acid Salts, phosphates, carbonates, etc.), lower alkyl sulfonates (methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.), aryl sulfonates (benzenesulfonate, paratoluene) Sulfonates, etc.), organic acid salts (such as fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.) or amino acid salts (glutamate, aspartate, etc.) Can be mentioned.
  • hydrohalide hydrofluoride, hydrobromide, hydrobromide, etc.
  • inorganic acid nitrate, perchlorate, Sulfuric acid Salts, phosphates, carbonates, etc
  • Base addition salts include, for example, alkali metal salts (sodium salts, strong lithium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), ammonium salts, or organic bases (guanidine, Triethylamine, dicyclohexylamine, etc.) addition salts.
  • the compounds of the present invention may exist as any hydrate or solvate of the free compound or salt thereof.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be administered orally or parenterally.
  • the compound of the present invention When the compound of the present invention is used clinically, it may be formulated by adding a pharmaceutically acceptable additive according to the administration form.
  • various additives that are usually used in the pharmaceutical field can be used.
  • the mixture of the compound of the present invention and the above-mentioned additive is used as a solid preparation (tablet, capsule, condyle, powder, suppository, etc.) or liquid preparation (syrup, elixir, injection, etc.) Can do.
  • These preparations can be prepared according to usual methods in the pharmaceutical field.
  • the liquid preparation may be dissolved or suspended in water or other appropriate medium at the time of use.
  • they may be dissolved or suspended in physiological saline or glucose solution as necessary, and buffering agents and preservatives may be added.
  • These formulations contain 1.0 to 100% by weight, preferably 1.0 to 60% by weight of the compound of the invention. /. It can contain in the ratio.
  • the compound of the present invention can be formulated according to the following formulation examples. (Formulation Example 1)
  • formulations may also contain other therapeutically effective drugs as described below.
  • the compounds of the present invention can be used in combination with other drugs useful for the treatment (prevention or treatment) of metabolic disorders or eating disorders.
  • the individual components in such combinations can be administered in divided or single formulations during the treatment period, at different times or simultaneously.
  • Combinations of the compounds of the present invention with other drugs useful for the treatment of metabolic disorders or eating disorders also include combinations of drugs that are in principle not useful for the treatment of metabolic disorders or eating disorders.
  • the compounds of the present invention are also effective drugs for hypertension, obesity-related hypertension, hypertension-related diseases, cardiac hypertrophy, left ventricular hypertrophy, metabolic diseases, obesity, obesity-related diseases, etc.
  • compositions containing the compound of the present invention and the concomitant drug may be administered simultaneously or separately or sequentially to the administration subject. That In this case, the composition and the concomitant drug may be packaged separately. They can be administered at a time interval.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination, and the like.
  • the administration form of the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such dosage forms include 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) formulating the compound of the present invention and the concomitant drug separately.
  • Simultaneous administration of the two obtained preparations by the same administration route 3) Administration of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug at the same administration route with a time difference 4) Obtained by separately formulating the compound of the present invention and the concomitant drug 2.
  • Simultaneous administration of different preparations by different administration routes 5) Formulating the compound of the present invention and the concomitant drug separately Administration of the obtained two types of preparations at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention and concomitant drug, or administration in the reverse order).
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the concomitant drug used in the present invention include antidiabetic drugs, hyperlipidemia drugs, hypertension drugs, anti-obesity drugs and the like. Two or more of these concomitant drugs may be used in combination at an appropriate ratio.
  • antidiabetics include, for example,
  • Grippen clamide (g 1 ibencl am ide), Daribizide (g 1 ipi zide), glyburide (g 1 yburide), glimepiride (g 1 i me piride), dali clazide (g 1 ic 1 azide), dali pendide (g 1 ipentide), glyquidone (g 1 iquidone), glysolamide (g 1 isolamide) ), Sulfonylureas such as tolazamide and tolptamide, 5) meglitinides such as reno, ° glinide (repag 1 inide), nateglinide (nateg 1 inide),
  • acarbose adiposine ', force miglibose (camiglibose), emiglitate (emig ⁇ 1 itate), migli tonole (mig 1 ito' 1), voglibose.
  • Vog 1 ibose pradimicin Q (pradimicin in Q — Q), 'Salbostatin, CKD— 7 1 1, MDL— 2 5, 6 7 3, MD L— 7 3, 94 5, ⁇ -Dalcoside hydrolase inhibitors such as M ⁇ R 1 4,
  • ⁇ -amylase inhibitors such as tendamistat (t e n d a m i t tat;), trestatin (t e e r tat i n), A 1 36 8 8, etc.
  • Fatty acid oxidation inhibitors such as cucumber moxinore (c 1 o m o X i r), etomoxinore (e t.omo x i r),
  • A2 Antagonis such as midaglizole, isagridole (isag 1 ido 1 e), deridlidole (), idazoxan, earoxan, and ⁇ fnorenoloxane (f 1 uparo X an) G
  • JT_ 50 non-thazolidinediones such as phenoleglitazole (f a r g l i t a z a r),
  • antihyperlipidemic agent examples include:
  • Cholesterol absorption inhibitors such as snatonore estenole, sitostero / re, stellonoregnorecoside, ezetimibe,
  • AC AT Asinore C o A ⁇ Cholesterol lucifer transferase
  • C TT inhibitors such as J TT 700, Torcetrabib (tor c e tr ra ap i b), CP 5 3 26 3 2, BAY— 6 3— 2 1 4 9, S C— 5 9 1, S C— 7 9 5
  • F X R receptor antagonists such as GW—4 064, S R—1 0 3 9 1 2
  • Lipoprotein synthesis inhibitors such as niacin, 1 3) renin-angiotensin system inhibitor,
  • Bile acid reabsorption inhibitors such as D 7 706
  • P PAR Sagost such as GW50 1 5 1 6, GW 5 90 7 3 5
  • antihypertensive drugs examples include:
  • Betazoronole (beta X o 1 o 1), Benotonto mouthinole (bevantolol), Pisopro mouthinole (bisoprolol), Bopindololole, Power (carteolol), canole beshirono carvedi 1 o 1), serif.
  • Elopro Eeliprolol
  • Esmolo Esmolo
  • Intenol Mouth indenolol
  • Metapro Mouth Nepro
  • Nadoro Nadolol
  • Nevibo Mouth Nebivo 1 o 1
  • penbutolol pindronore
  • prono ronore sotaroro nore
  • taitaronore tertatolol
  • chile solo-nore ti 1 iso 1 o 1
  • J3 a drainage blocker
  • Tezosentan (t ezo o s e n t a n), A 3 0 8 1 6 5, YM6 2 8 9 9 etc.
  • Vasodilators such as hydralazine, clonidine, minoxidil, nicotul alcohol,
  • Niprazirol alotinolol, amosulalol, etc./]3 adrenaline blocker,.
  • anti-obesity drugs examples include
  • MCH-1R melanin-concentrating hormone receptor 1 antagonist, such as the compound disclosed in No. 69,
  • MCH-2R melanin-concentrating hormone receptor 2
  • Leptin such as human recombinant leptin (P EG— ⁇ B, HoffmanL a Roche), recombinant leptin (Amgen),
  • nalmefene R e V e X (registered trademark)
  • 3-methoxynal trexone naloxone
  • naltrexone compounds such as compounds disclosed in WO 0 0/2 1 5 0 9,
  • CNTF derivatives such as compounds disclosed in WO 98/22 1 28 and WO 99/438 13
  • GHS growth hormone secretagogue receptor
  • 5HT2c (Se P ⁇ nin receptor 2c) agonists such as compounds disclosed in / 40456 and W02 / 40457
  • Mc 4 r (melanocortin 4 receptor) agonist, such as the compounds disclosed in
  • Phytofarm compound 5 7 (ph y t o p h arm) (e.g., C P 6 4 4, 6 7 3),
  • AD 9 6 7 7 / TAK 6 7 7 (Dainippon Pharmaceutical / Takeda Pharmaceutical), CL— 3 1 6, 2 4 3, s B 4 1 8 7 90, BR L- 3 7 3 4 4, L — 7 9 6 5 6 8, BMS-
  • PDE phosphodiesterase
  • amylinone amrinone
  • milrinone milrinone
  • cinorestatide ci 1 ostamide
  • oral piperam ro 1 ipram
  • siromilast ci 1 omi 1 ast
  • Aged estrogen such as a genius rénoires ⁇ ron (disclosed in dl Mar-G r a sa, M e t a 1., Ob e s t y R e s e a r c h, 9: 202—9 (2001)
  • BVT3498 BVT2733, other compounds such as compounds disclosed in WOO 1 90091, WO0 1Z90090, WOO 1 90092, etc. 1 1—3 HSD 1 (1 1— / 3 Hydroxysystemoid Dehydrogenase Type 1) Inhibitor,
  • Tetrahydrolliptatin (or 1 istat / Xe nical (registered trademark)), Trito nWR 1 339, RHC 80267 Lipstatin, Teasaponin, Jetino reunbelliferinorephosphate (diethyl umo el 1 iferylpnosphate), r L— 0 8, WAY- 1 2 1 898, Bay— N— 31 76, valilactone, esteracin, ebelactone A, eberlactone A, B (ebelactone B), RHC 8 0267, Other WO 01/77094, USP 4, 598, 089, US P 4 , 452, 8 1 3, US P 5, 51 2, 565, US P 5, 3.9 1, 57 1, USP 5, 602, 1 51, USP 4, 405, 644, US P 4, 189, 43 8 and Lipase inhibitors such as compounds disclosed in U SP4, 242, 453,
  • the compound of the present invention can be combined with one or more of the above concomitant drugs.
  • a combination of the compound of the present invention and one or more drugs selected from the group consisting of a therapeutic drug for diabetes and a therapeutic drug for hyperlipidemia is useful for the prevention or treatment of metabolic diseases.
  • a combination of the compound of the present invention and one or more drugs selected from the group consisting of a therapeutic drug for diabetes and a therapeutic drug for hyperlipidemia is useful for the prevention or treatment of metabolic diseases.
  • synergistic effects of preventing or treating metabolic diseases are achieved. Become. '
  • the dose and frequency of administration vary depending on the sex, age, weight, symptom of the patient, and the type and range of the desired treatment effect.
  • 0.01 to 10 OmgZkg per adult preferably 0.03 to lmgZkg
  • 0.001 to 1 OmgZkg preferably 0.001 to 0.1 mg "kg, is administered in 1 to several divided doses.
  • Thin layer chromatography in the examples was performed using Si 1 icage 160 F 245 (Me rck) as a plate and a UV detector as a detector.
  • Wa koge 1 TM C-300 (Wako Pure Chemicals) as silica gel for column, LC—SORBTM S PB-OD S (Chemco) or YMC—GE LTM ODS-AQ 120-S 50 (Yamamura) as silica gel for reversed phase column Chemical Laboratory).
  • the mass spectrum was measured by an electrospray ionization method (ES I) using Quattro II (manufactured by Micromass).
  • the NMR spectrum uses dimethyl sulfoxide as an internal standard when measuring with a deuterated dimethyl sulfoxide solution.
  • n-B ⁇ ⁇ -butynole group
  • the title compound was obtained by the method according to Example 1 using the compound obtained in Reference Example '1 (2) and N-methyl-N- (piberidinoethyl) amine as raw materials.
  • Example 2 Sodium hydride (10 mg) was added to ethanol (1.0 mL). This solution was added to a solution of the compound (40 mg) obtained in Example 1 in ethanol (1.OmL) and stirred at 65 ° C. for 18 hours. The pH was adjusted to 2 using 6N hydrochloric acid at 0 ° C. A saturated aqueous sodium bicarbonate solution was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 10 Using the compound obtained in Example 4 and methanol as raw materials, the title compound was obtained by the method according to Example 10.
  • the title compound was obtained by the method of Example 10 using the compound obtained in Example 4 and ethanol as raw materials.
  • the title compound was obtained by the method according to Example 10 using the compound obtained in Example 1 and methanol as raw materials.
  • the title compound was obtained by the method according to Example 15 using the compound obtained in Example 1 and dimethylamine as raw materials.
  • the title compound was obtained by the method of Example 15 using the compound obtained in Example 1 and piperidine as raw materials.
  • the title compound was obtained by the method of Example 15 using the compound obtained in Example 4 and piperidine as raw materials.
  • the title compound was obtained by the method according to Example 19 using the compound obtained in Example 4 and 3-hydroxypyridine as raw materials.
  • Example 2 1 Trans 1 5 '1 F 2 1 3 1 oxo 1 N-methino 1 N — (2 1 pyrrolidine 1 1 ylethyl)-spiro 1, 1 _ 1 (3' H)-4.
  • the title compound was obtained by the method according to Example 21 using the compound obtained in Example 4 and 4-fluorophenylboronic acid as raw materials.
  • the title compound was obtained by the method according to Example 21 using the compound obtained in Example 4 and 2-methoxy-5-pyridinepolonic acid as raw materials.
  • the title compound was obtained by the method according to Example 21 using the compound obtained in Example 4 and 4 (methansulfonyl) phenylboronic acid as starting materials.
  • the title compound was obtained by the method according to Example 21 using the compound obtained in Example 1 and 2-methoxy-5-pyridinepolonic acid as raw materials.
  • Example 21 using the compound obtained in Example 4 and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) 1 1H-pyrazole as raw materials The title compound was obtained by the method.
  • the title compound was obtained by the method according to Example 21 using the compound obtained in Example 4 and 2,4-dimethoxypyridine-5-boronic acid as raw materials.
  • the title compound was obtained by the method according to Example 1 using the compound obtained in Reference Example 3 and N-methyl- ⁇ - (piperidinoethyl) amine as raw materials.
  • the title compound was obtained by the method according to Example 1 using the compound obtained in Reference Example 3 and N-methyl-N- (pyrrolidinoethyl) amine as raw materials.
  • the title compound was obtained by the method according to Example 10 using the compound obtained in Example 32 and methanol as raw materials.
  • the title compound was obtained by the method according to Example 10 using the compound and methanol obtained in Example 33 as raw materials.
  • the title compound was obtained by the method according to Example 10 using the compound obtained in Example 32 and ethanol as raw materials.
  • the title compound was obtained by the method according to Example 10 using the compound obtained in Example 33 and ethanol as raw materials.
  • Example 3 Using the compound obtained in 2 and 2-propanol as raw materials, the title compound was obtained by the method according to Example 10.
  • 1 HNMR (40 MHz, CDC 1 3. ⁇ ): 1.40-1.49 (2H, m), 1.45 (6 H, d, J 6.3 H z), 1. 54-1. 64 (4 H, m), 1. 7 3— 1. 8 7 (2H, m) '1.
  • 9 4-2. 1 2 (4 H, m), 2. 2— 2. 3 4 (2 H, m), 2. 3 8— 2. 5 7 (6 H, m), 2. 88-2. 98 (1 H, m), 2. 9 7 (3H x lZ2, s), 3. 1 1 (3Hx 1/2, s), 3.44 (2Hx 1/2, t, J 7.
  • Example 33 Using the compound obtained in 3 and 2-propanol as raw materials, the title compound was obtained by the method according to Example 10.
  • the title compound was obtained by the method according to Example 10 using the compound obtained in Example 33 and cyclopropanemethanol as raw materials. ''
  • the title compound was obtained by the method according to Example 21 using the compound obtained in Example 32 and trimethylboroxine as raw materials.
  • the title compound was obtained by the method according to Example 30 using the compound obtained in Example 33 as a starting material.
  • the title compound was obtained by the method according to Example 21 using the compound obtained in Example 32 and phenylboronic acid as raw materials.
  • the title compound was obtained by the method according to Example 21 using the compound obtained in Example 33 and (4 monofluorophenyl) boronic acid as raw materials.
  • Example 21 Using the compound obtained in Example 3 2 and (1-methyl-1 H-pyrazole-4-yl) boronic acid as a starting material, the title compound was obtained by the method according to Example 21. 'HNMR (4 00 MHz, CDC 1 3 , ⁇ ) 1.4 0—1.5 0 (2 H, m), 1.5 4-1. 6 4 (4 H, m), 1. 7 5 -1. 8 6 (2 H, m), 1. 9 8-2. 1 5 (4 H, m), 2. 3 1-2.5 6 (8 H, m), 2. 9 3-3 .
  • the title compound was obtained by the method according to Example 19 using the compound and phenol obtained in Example 32 as raw materials.
  • Example 33 Using the compound obtained in 3 and 4 monofluorophenol as raw materials, Example 19 The title compound was obtained by a method according to 9.
  • the title compound was obtained by a method according to Example 15 using the compound obtained in Example 32 and pyrrolidine as raw materials.
  • the title compound was obtained by the method according to Example 15 using the compound obtained in Example 33 and pyrrolidine as raw materials.
  • Example 15 I Using the compound and morpholine obtained in Example 32 as raw materials, the title compound was obtained by a method according to Example 15 I :.
  • the title compound was obtained by the method according to Example 21 using the compound obtained in Example 1 and 3-pyridineboronic acid as raw materials.
  • the title compound was obtained by the method according to Example 21 using the compound obtained in Example 4 and 3-pyridineboronic acid as raw materials.
  • Example 21 The title compound was obtained in the same manner as in Example 21 using the compound obtained in Example 4 and 2- (tree n-butyltin) virazine as raw materials.
  • Example 5 The compound (440 mg) obtained in 5 was dissolved in ethyl acetate (10 mL) and methanol (10 mL), and 10% palladium on carbon (2500 mg) was added, and hydrogen atmosphere was added. The mixture was stirred at room temperature for 2 hours. The catalyst was filtered and concentrated under reduced pressure to give the title compound (33 1 mg, 100%) as a colorless solid.
  • the reaction solution was concentrated under reduced pressure, water and black-form were added, and neutralized with potassium carbonate.
  • the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the obtained solid was suspended in ethyl acetate and then collected by filtration to obtain the target compound (3.889 g, 65%) as a colorless solid.

Abstract

L’invention concerne un composé représenté par la formule (I) ci-dessous ou un de ses sels pharmaceutiquement acceptables. (I) [Dans la formule, X, Y, Z et W représentent indépendamment un groupement méthine ou un atome d'azote, tous les X, Y, Z et W n’étant pas en même temps des groupements méthine ; A représente -O- ou analogue ; B représente -C(O)- ou analogue ; D représente -(CH2)m2-, -O- ou analogue ; et m2 représente 0 ou 1 ; Q représente un groupement méthine ou un atome d’azote ; et R représente un groupement représenté par la formule suivante (II-1) : (II-1) (dans laquelle R6, R7 et R8 représentent indépendamment un groupement alkyle inférieur ou analogue).]
PCT/JP2006/322911 2005-11-10 2006-11-10 Derive spiro aza-substitue WO2007055418A1 (fr)

Priority Applications (12)

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US12/084,817 US8158791B2 (en) 2005-11-10 2006-11-10 Aza-substituted spiro derivatives
CA2629018A CA2629018C (fr) 2005-11-10 2006-11-10 Derive spiro aza-substitue
AU2006312557A AU2006312557B2 (en) 2005-11-10 2006-11-10 Aza-substituted spiro derivative
ES06832790T ES2381205T3 (es) 2005-11-10 2006-11-10 Derivado espiro aza-sustituido
NZ568292A NZ568292A (en) 2005-11-10 2006-11-10 Spiro[cyclohexane-1,1'-(3'H)-4'-azaisobenzofuran]-4-carboxamide derivatives
EP06832790A EP1953165B1 (fr) 2005-11-10 2006-11-10 Derive spiro aza-substitue
JP2007544242A JP4371164B2 (ja) 2005-11-10 2006-11-10 アザ置換スピロ誘導体
KR1020087011108A KR101318127B1 (ko) 2005-11-10 2006-11-10 아자 치환된 스피로 유도체
BRPI0618354A BRPI0618354B8 (pt) 2005-11-10 2006-11-10 composto e seu uso, composição farmacêutica, preventivo ou remédio
CN200680041873.0A CN101305009B (zh) 2005-11-10 2006-11-10 氮杂取代的螺环衍生物
NO20082579A NO20082579L (no) 2005-11-10 2008-06-09 Aza-substituert spiroderivat
US13/396,887 US20120149703A1 (en) 2005-11-10 2012-02-15 Aza-substituted spiro derivatives

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JP2005325808 2005-11-10
JP2005-325808 2005-11-10
JP2006-060814 2006-03-07
JP2006060814 2006-03-07

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JP (1) JP4371164B2 (fr)
KR (1) KR101318127B1 (fr)
AU (1) AU2006312557B2 (fr)
BR (1) BRPI0618354B8 (fr)
CA (1) CA2629018C (fr)
CR (1) CR9961A (fr)
EC (1) ECSP088438A (fr)
ES (1) ES2381205T3 (fr)
GT (1) GT200800060A (fr)
MA (1) MA30029B1 (fr)
MY (1) MY146564A (fr)
NO (1) NO20082579L (fr)
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